Inhibition of selenoprotein P expression by monocarbonyl curcumin derivatives through covalent modification of selenium-metabolism enzymes and their potential anti-diabetic effects

Overproduction of selenoprotein P (SeP, encoded by Selenop), a selenium transport protein secreted by the liver, functions as a hepatokine and has been implicated as a therapeutic target for type 2 diabetes. Compounds that suppress SeP expression may therefore have value in preventing or treating diabetes. In this study, we screened a monocarbonyl curcuminoid library and identified the monocarbonyl curcumin derivative GO-Y015 as the most potent and least toxic SeP inhibitor. Unlike diketone curcumin, GO-Y015 exerted robust SeP-suppressive effects in cultured cells. Pull-down assays using biotin-linked GO-Y015 demonstrated covalent binding to PRDX6, SCLY, and SEPHS2—key enzymes required for de novo selenoprotein biosynthesis—suggesting that GO-Y015 inhibits the selenium metabolic pathway at multiple points. In KK-Ay diabetic mice, GO-Y015 administration reduced circulating SeP levels and improved glucose metabolism, as evidenced by improved glucose and insulin tolerance. Together, these findings identify GO-Y015 as a promising inhibitor of excessive selenium metabolism with therapeutic potential for diabetes.